Project Summary/ Abstract ! Traumatic brain injuries (TBI), that occur at a rate of greater than 2 million per year, and the serious clinical problems that occur after TBI, affect approximately 5 million people in the U.S.! alone. Currently, there are no effective therapies. We have discovered that the immune system may directly contribute to inflammation and degeneration of the brain, and behavioral deficits following TBI. More specifically, we found that CD74, a protein involved in both the innate and adaptive immune responses, may contribute to acute, early and chronic pathologies that result from TBI. The rationale for the current proposal is based on three observations: 1) data indicating that depleting CD74 is anti-inflammatory a neuroprotective after TBI; 2) evidence from human clinical TBI patients showing strong evidence of an adaptive immune response after TBI; and 3) Our preliminary data that implicate CD74 in chronic pathologies after TBI. We seek to revolutionize the understanding of TBI- pathology, and to identify potential targets for therapeutic intervention by testing our overarching hypothesis that CD74 contributes to the innate and adaptive immune responses following TBI and can be targeted to create novel therapies for treatment. Using our established mouse model of brain injury, the fluid percussion injury (FPI) model, we propose to test our hypothesis using the following Specific Aims: (1) to deteremine the distinct contributions of full-length CD74, CLIPs, and MHCII, to the innate and adaptive immune responses after brain trauma injury, (2) to determine the impacts of these CD74-related mechanisms on neuropathology and behavioral outcomes, and (3) to determine the contributions of activated B and T cells following TBI. Relevance: Based on the urgent clinical need for treatments following TBI, these studies are important because they have the potential to transform our understanding of the innate and adaptive immune response after TBI, and because CD74 may provide a novel therapeutic target for treating TBI and post traumatic behavioral syndromes.